Clostridial neurotoxins interfere with regulated secretion and membrane trafficking, and are models to study protein sorting, transport, and targeting. Each of the toxins blocks vesicular neurotransmitter release, cleaves a specific protein implicated in synaptic vesicle docking/fusion, and prevents the fusion of synaptic vesicles with the presynaptic membrane. Botulinum neurotoxin C is unique in that it proteolyzes two proteins (SNAP-25 and syntaxin) and is severely cytotoxic to both developing and mature neurons in cell culture. Studies with botulinum neurotoxin A, which uncouples synaptic vesicle endocytosis from exocytosis, demonstrate that vesicle membrane recycling by endocytosis is dependent on calcium. Botulinum neurotoxins E and F fail to inhibit transmitter release from spinal cord cell cultures but act effectively to block nerve-muscle synapses. Neuronal membrane gangliosides play an important role in tetanus toxin internalization and may be a functional component of the toxin receptor.